Combined effects of the oral fluoropyrimidine anticancer agent, S-1 and radiation on human oral cancer cells

Harada, Koji; Kawaguchi, Shinichi; Supriatno, .; Onoue, Takeshi; Yoshida, Hideo; Sato, Mitsunobu

doi:10.1016/j.oraloncology.2004.01.013

Cited by 47 publications

(36 citation statements)

References 12 publications

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“…Several reports have suggested that chemoradiotherapy using S-1 in combination with X-ray irradiation is fairly effective against various types of cancer xenografts, and its anticancer effects are mediated by mechanisms including induction of apoptosis, inhibition of survival signals or suppression of radiation-induced hypoxia-inducible factor-1 (HIF-1) activation (22)(23)(24)(25). Preliminary clinical studies have demonstrated the potential efficacy of chemoradiotherapy with S-1 and radiation in treating locally advanced head and neck and pancreatic cancers (26,27).…”

Section: Introductionmentioning

confidence: 99%

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

Fukushima

Sakamoto²,

Sakata³

et al. 2010

Oncol Rep

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Abstract. Chemoradiotherapy is a useful treatment strategy in patients with locally advanced cancers. In particular, combination of 5-fluorouracil (5-FU) with X-ray irradiation is effective for the treatment of some types of gastrointestinal cancers. We investigated the antitumor effects of combination treatment with X-ray and S-1, a unique formulation of 5-FU, on human cancer xenografts in nude mice and compared the efficacy of this treatment to that of radiotherapy combined with cisplatin, UFT, another oral 5-FU prodrug, and intravenous 5-FU. Tumors implanted into the left hind legs of mice were treated with a dose of 2 or 5 Gy X-ray irradiation on days 1 and 8, and S-1, UFT and 5-FU were administered for 14 days. The efficacy of combined treatment with 8.3 mg/kg S-1 and 2 Gy X-ray irradiation in treating non-small cell lung cancer xenografts (Lu-99 and LC-11) was significantly higher than that of treatment with S-1 alone or 2 Gy X-ray irradiation alone, and the antitumor activity of combined treatment was similar to that of 5 Gy X-ray irradiation alone. Although 8.3 mg/kg S-1 and 17.5 mg/kg UFT had equivalent antitumor activity; the antitumor efficacy of combination treatment with S-1 and 2 Gy X-ray irradiation on LC-11 tumors was significantly higher than that of combination treatment with UFT and 2 Gy X-ray irradiation. Combination treatment with S-1 and X-ray irradiation was also more effective against pancreatic tumors than combination treatment with intravenous 5-FU and X-ray irradiation. To elucidate the reason for the increased antitumor efficacy of combination treatment with S-1 and X-ray irradiation, the antitumor effect of gimeracil, one of the components of S-1, was tested in combination with 2 Gy X-ray irradiation. These experiments demonstrated that gimeracil enhanced the efficacy of X-ray irradiation against lung as well as head and neck cancer xenografts in a dosedependent manner. Furthermore, we observed decreased expression of Á-H2AX protein, a marker of DNA repair, in LC-11 tumors treated with X-ray irradiation and gimeracil compared to that observed in tumors treated with X-ray irradiation alone, suggesting that gimeracil may inhibit rapid repair of X-ray-induced DNA damage in tumors. The present study suggests that chemoradiotherapy using S-1 acts through a novel mechanism and may prove useful in treating patients with locally advanced cancers whose disease progression is difficult to control using chemotherapy alone.

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Section: Introductionmentioning

confidence: 99%

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

Fukushima

Sakamoto²,

Sakata³

et al. 2010

Oncol Rep

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“…It is considered to be beneficial because of its convenience of being administered by the oral route. In addition, combined S-1 and radiotherapy has been demonstrated to exert a synergistic effect against 5-FU-resistant cancer xenografts (Harada et al, 2004;Nakata et al, 2006). Therefore, a clinical trial of concurrent radiotherapy with S-1 therapy for locally advanced PC was designed to intensify the treatment efficacy and improve the convenience of administration.…”

Section: Discussionmentioning

confidence: 99%

A phase I trial of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer

Ikeda¹,

Okusaka²,

Ito

et al. 2007

Br J Cancer

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This study investigated the maximum tolerated dose of S-1 based on the frequency of its dose-limiting toxicities (DLT) with concurrent radiotherapy in patients with locally advanced pancreatic cancer. S-1 was administered orally at escalating doses from 50 to 80 mg m À2 b.i.d. on the day of irradiation during radiotherapy. Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks, and no prophylactic nodal irradiation was given. Twenty-one patients (50 three; 60 five; 70 six; 80 mg m À2 seven patients) were enrolled in this trial. At a dose of 70 mg m À2 S-1, two of six patients demonstrated DLT involving grade 3 nausea and vomiting and grade 3 haemorrhagic gastritis, whereas no patients at doses other than 70 mg m À2 demonstrated any sign of DLT. Among the 21 enrolled patients, four (19.0%) showed a partial response. The median progression-free survival time and median survival time for the patients overall were 8.9 and 11.0 months, respectively. The recommended dose of S-1 therapy with concurrent radiotherapy is 80 mg m À2 day À1. A multi-institutional phase II trial of this regimen in patients with locally advanced pancreatic cancer is now underway.

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“…Thus, S-1 may also act as a radiosensitizer because it has cytotoxic mechanisms similar to those of 5-FU (Hirata et al, 1999;Hoff et al, 2003;Schoffski, 2004). Harada et al (2004) evaluated S-1 in combination with ionising radiation both in vivo and in vitro against human oral cancer cell lines. They showed that the combination of S-1 and radiation was more effective than either agent alone, and that S-1 administration before radiation was more effective than administration after radiation.…”

Section: Discussionmentioning

confidence: 99%

“…S-1 has also been shown to be a potent radiosensitizer in human solid tumour xenograft (Fukushima et al, 1998;Harada et al, 2004), which suggests that the combination of radiotherapy and S-1 may improve survival in patients with locally advanced pancreatic cancer. However, no previous reports have described the efficacy and safety of chemoradiation therapy with S-1 for the treatment of pancreatic cancer.…”

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confidence: 99%

Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer

et al. 2007

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In this phase-I trial, we evaluated the safety of S-1, a novel oral fluoropyrimidine anticancer agent, combined with external-beam radiotherapy (EBRT) to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients. Patients had histologically proven unresectable locally advanced or metastatic pancreatic cancer. S-1 was administered orally twice daily. External-beam radiotherapy was delivered in fractions of 1.25 Gy Â 2 per day, totalling 50 Gy per 40 fractions for 4 weeks. S-1 was given at five dose levels: 60 mg m -2 day -1 on days 1 -7 and 15 -21 (level 1), 1 -14 (level 2), and 1 -21 (level 3a) and 80 mg m -2 day -1 on days 1 -21 (level 3b) and 1 -28 (level 4). We studied 17 patients: dose levels 1 (four patients), 2 (four patients), 3a (three patients), 3b (three patients), and 4 (three patients). One patient in level 1 (grade 3 vomiting) and two patients in level 4 (grade 4 neutropenia and grade 3 anorexia) showed DLT. No DLT was seen for levels 2, 3a, and 3b. Clinical effects by computed tomography included 5 partial responses (35%), 11 cases of stable disease, and one case of progressive disease. CA19 -9 levels of less than half the starting values were observed in 8 of 16 (50%) patients. S-1 at a dose of 80 mg m -2 day -1 given on days 1 -21 is safe and recommended for phase-II study in patients with locally advanced and unresectable pancreatic cancer when given with EBRT.

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Combined effects of the oral fluoropyrimidine anticancer agent, S-1 and radiation on human oral cancer cells

Cited by 47 publications

References 12 publications

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

A phase I trial of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer

Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer

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